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© 1998 Nature America Inc. • http://neurosci.nature.com
articles
Plasticity of temporal information
processing in the primary auditory
cortex
Michael P. Kilgard1 and Michael M. Merzenich1,2
1
Coleman Laboratory, Departments of Otolaryngology and Physiology, Keck Center for Integrative Neuroscience,
University of California at San Francisco, San Francisco, California 94143-0444, USA
2
Scientific Learning Corporation, 1995 University Avenue, Berkeley, California 94104-1075, USA
© 1998 Nature America Inc. • http://neurosci.nature.com
Correspondence should be addressed to M.P.K. ([email protected])
Neurons in the rat primary auditory cortex (A1) generally cannot respond to tone sequences faster
than 12 pulses per second (pps). To test whether experience can modify this maximum following
rate in adult rats, trains of brief tones with random carrier frequency but fixed repetition rate were
paired with electrical stimulation of the nucleus basalis (NB) 300 to 400 times per day for 20–25
days. Pairing NB stimulation with 5-pps stimuli markedly decreased the cortical response to rapidly
presented stimuli, whereas pairing with 15-pps stimuli significantly increased the maximum cortical
following rate. In contrast, pairing with fixed carrier frequency 15-pps trains did not significantly
increase the mean maximum following rate. Thus this protocol elicits extensive cortical remodeling
of temporal response properties and demonstrates that simple differences in spectral and temporal
features of the sensory input can drive very different cortical reorganizations.
Most studies of cortical plasticity have documented changes
evoked by spatially or spectrally specific stimuli1–7. In one such
experiment, we demonstrated that pairing NB activation with
tonal stimulation in a non-behaving rat can greatly expand the
representation of a given tone frequency in A1 and cause largescale remodeling of the spectral selectivity of A1 receptive fields
(frequency–intensity tuning curves)8 (see also refs 9, 10 from
others). The NB neurons, located in the basal forebrain, send
cholinergic and GABAergic projections to the entire cortical mantle11 (Fig. 1a). Pairing NB stimulation with sound stimulation
failed to produce significant cortical reorganizations when the
acetylcholine-containing cells in the NB were immunolesioned8.
Together, these studies support the long-standing view that the
cholinergic projection from the NB is a primary modulatory
input that enables experience-dependent cortical plasticity.
Here we used NB activation to explore the principles governing the plasticity of cortical dynamics as they apply to the representation of the temporal features of rapid, successive stimulus
events. One method of describing the capacity of cortical neurons to respond to successive inputs is to derive a ‘repetition-rate
transfer function’ (RRTF), in which the neural discharge rate is
defined as a function of the stimulus repetition rate. Depending
upon the type of stimulus modulation used, RRTFs derived for
neurons in the primary visual, auditory or somatosensory cortices are low-pass (responding only to stimuli below a certain
rate) or band-pass (responding best to rates over a limited
range)12–19. In the primary visual and auditory cortical areas,
most neurons respond maximally to repeated stimuli when they
are presented at 7–12 pps, responding progressively more poorly at higher repetition rates.
Because the RRTFs of cortical neurons reflect sequences of
excitatory and inhibitory cortical circuit events that are set in
nature neuroscience • volume 1 no 8 • december 1998
motion when the cortex is abruptly engaged by a stimulus12,17,18,20–25, one might predict that this elemental input sampling/recovery property of cortical circuits is immutable.
However, a large body of evidence has indicated that temporal
response properties of cortical neurons can be substantially
altered by experience. For instance, the visual cortex of visually
deprived animals responds poorly to stimuli repeated at rates
above 5 pps26,27. Furthermore, psychophysical studies show that
training can improve the ability to discriminate differences in
rate, stimulus duration or interval separating successively presented stimuli, consistent with progressive improvements in cortical processing of temporal information28–32. For example, with
practice, subjects are able to detect brief auditory or visual stimuli that are followed at progressively shorter times by intense
masking stimuli, consistent with a several-fold training-induced
decrease in cortical integration time33,34. Monkeys trained to
detect changes in amplitude modulation rate show sharper and
stronger cortical responses to the trained modulation rate35, and
this strengthening of cortical responses strongly correlates with
improved task performance.
Such changes in temporal properties of cortical responses
could result from plasticity of synaptic, intrinsic or network
time constants. For example, plasticity of excitatory synapses
onto inhibitory neurons36–38 and of inhibitory synapses themselves39 may shape the responses of cortical neurons to rapidly successive stimuli in vivo 40,41 . Additionally, presynaptic
release probability contributes to the cortical response to successive inputs and shows experience-dependent plasticity42,43.
Together these experiments indicate that the capacity of the
cortex to respond to successive events in time is shaped by a
succession of excitatory and inhibitory processes, whose
dynamics can be modified by experience.
727
© 1998 Nature America Inc. • http://neurosci.nature.com
articles
a
a
b
Cortex
CPu
GP
Thal
C
Fig. 1. Response of rat
auditory cortex neurons
to
repeated
stimuli.
(a) Schematic diagram of
the projection of nucleus
basalis to the neocortex.
(b) Number of rats and
penetrations for each
experimental
condition.
(c) Dot rasters and repetition-rate transfer function
(RRTF) of primary auditory
cortex (A1) neurons from
a naïve (control) rat. Each dot represents a single action potential. The
short horizontal lines indicate the
spike-collection windows that were
used to generate the RRTF. The RRTF
quantifies the generally low-pass nature
of the responses of A1 cortical neurons
to these pulsed stimuli in the rat. The
solid vertical line in the RRTF shows the
average number of spikes evoked by the
first tone in the train. (d) Mean normalized RRTF for all penetrations recorded
from normal (control) rats. Error bars
indicate standard errors.
Repetition rate (pps)
Repetition rate (pps)
d
Results
In this study, NB activation was paired with temporally modulated acoustic stimuli to investigate plasticity of the cortical representation of time-varying information. Stimulating electrodes
were chronically implanted in the right NB of 15 adult rats. After
recovery, animals were placed in a sound-attenuation chamber,
and trains of six tone bursts were paired with NB stimulation
during daily sessions. Tone trains and NB stimulation occurred
randomly every 8–40 seconds, repeated three- to four-hundred
times per day for 20–25 days. Rats were unanesthetized and unrestrained throughout this procedure. The train repetition rate for
each rat was fixed at 5, 7.5 or 15 pps. The tonal (carrier) frequency
was varied randomly trial by trial. The seven carrier frequencies
that were used extended across most of the frequency range represented in the primary auditory cortex (A1) of the rat. Twentyfour hours after the last pairing session, each animal was
anesthetized, and the responses of A1 neurons were recorded
from 30–60 microelectrode penetrations distributed evenly across
A1. Frequency–intensity tuning curves and RRTFs were derived
to characterize the spectral and temporal response properties of
neurons in every penetration.
In naïve animals, at repetition rates up to about 9 pps, each
brief tone generally evoked the same number of spikes from
728
Spikes/tone
ms
Normalized spike rate
© 1998 Nature America Inc. • http://neurosci.nature.com
Nucleus
Basalis
Repetition rate (pps)
A1 neurons as did the first tone in the train (Fig. 1). At repetition rates from 9 to 14 pps, the number of spikes per tone fell
off rapidly, and only neurons at rare sites responded at all to
rates above 15 pps. In experimental rats, exposure to 15-pps
stimuli at variable carrier frequencies paired with NB stimulation markedly altered the temporal responses of cortical neurons recorded all across A1. Although no specific response peak
emerged at 15 pps, the cut-off rate of low-pass RRTFs in A1
rose significantly in most sampled neurons. In striking contrast to control rats, the average neuron in these samples
responded strongly to repetition rates between 10 and 20 pps
(Fig. 2a). This increase in the neural response to 15-pps trains
after pairing was highly significant (p < 0.0001; Fig. 2c). The
high-rate slope of the average RRTF shifted up, reflecting a
strong response improvement across a broad range of higher
modulation frequencies (Fig. 2a and c).
To determine whether or not NB-induced temporal plasticity is specific to the repetition rate of the paired acoustic stimulus, 5-pps trains were paired with NB activation. The normalized
response evoked by stimuli repeated at 5 pps was increased significantly (p < 0.01), resulting in RRTFs with bandpass characteristics (response maxima near 5 pps). The 5-pps pairing resulted
in two distinct classes of cortical responsiveness to faster rates.
nature neuroscience • volume 1 no 8 • december 1998
© 1998 Nature America Inc. • http://neurosci.nature.com
articles
RepetitionRate
rate(pps)
(pps)
Repetition
0
100
200
300
400
500
600
700
5
10
15
20
0
RepetitionRate
rate (pps)
(pps)
Repetition
Repetition rate
Repetition
Rate(pps)
(pps)
0
c
NormalizedSpike
spike Rate
rate
Normalized
© 1998 Nature America Inc. • http://neurosci.nature.com
Repetition
rate
(pps)
Repetition
Rate
(pps)
Fig. 2. Temporal response
a 3.2
plasticity
induced
by
6.8
nucleus basalis stimulation.
(a) Response to repeated
8.4
tones after pairing NB stim9.8
ulation with 15-pps trains
applied at 7 different carrier
11.1
frequencies. The maximum
13.9
following rate and the range
16.9
over which strong stimulusby-stimulus responses were
-100
evoked was increased all
across A1 in this sample,
b
compared to controls.
3.2
(b) Response to repeated
6.8
tones after pairing NB stimulation with 5-pps trains of
8.4
tones at a randomly varied
9.8
carrier frequency. The max11.1
imum following rate was
significantly decreased com13.9
pared to controls. (c) Mean
16.9
normalized RRTFs for penetrations recorded from ani-100
mals that received NB
stimulation paired with 5-,
7.5- or 15-pps trains of tone
(carrier) frequencies that varied from
train to train, compared to control
RRTFs. The RRTF of each site was normalized using the number of spikes
evoked by the first tone in each train.
Error bars indicate standard error. The
rates that were significantly different from
controls are marked with dots (one-way
ANOVA, Fisher’s PLSD, p < 0.05).
100
200
300
400
ms
Milliseconds
500
600
700
2
4
5
10
15
20
0
2
Spikes/tone
Spikes/Tone
1.2
1
0.8
0.6
0.4
Control
5 pps
7.5 pps
15 pps
0.2
In three of four animals, the entire RRTF was shifted leftward,
causing significantly lower maximum following rates (Fig. 2b
and c). In the remaining animal, 75% of sites showed strong facilitation to both 5- and 10-pps stimuli, but poor responses to stimuli repeated at 7.5 pps (data not shown). Thus NB-induced
plasticity reliably increased the strength of the cortical response to
stimuli presented at the paired rate, even though the RRTF plasticity took two different forms.
Pairing 7.5-pps stimuli at randomly varied carrier frequency
with NB stimulation selectively strengthened the cortical response
to stimuli repeated at rates near 7.5 pps. The mean RRTF again
took a bandpass form, with a substantially stronger-than-normal response to modulated stimuli emerging at the paired stimulus rate (Fig. 2c). The normalized response of 1.2 indicates that
20% more spikes were evoked on average by each tone in the context of a 7-pps train compared to the same tone in isolation.
As reported previously, pairing tones at 15 pps with a constant
carrier frequency of 9 kHz markedly enlarged the region of A1
representing 9 kHz in every animal8. Surprisingly, pairing NB
stimulation with trains of 9-kHz tones repeated at 15 pps did not
nature neuroscience • volume 1 no 8 • december 1998
3
5
7
9
11
13
RepetitionRate
rate (pps)
Repetition
(pps)
15
17
19
cause the rightward shift in the mean RRTF that resulted from
pairing NB stimulation with multiple-frequency trains repeated at
15 pps. No significant alteration in the mean response to the
paired repetition rate (15 pps) was detected in the population
RRTF analysis (0.27 versus 0.28, p > 0.5; one-way ANOVA).
Although it is unclear how topographic map reorganization and
temporal plasticity are related, it is interesting to note that pairing
random-frequency 15-pps trains with NB stimulation significantly increased the maximum stimulus following rate of cortical neurons, but did not systematically alter the A1 frequency map.
Discussion
Paired NB and sensory stimulation provides a simple model system for studying the rules that operate in the cortex to transform
sensory input structure and schedules into distributed cortical
response patterns. Previous studies focusing on the plasticity of
the cortical representation of spectral information have demonstrated that cholinergic modulation is sufficient to shift A1 tuning curves toward the frequency paired with NB
stimulation8–10,44,45. In this study, we used NB activation to
729
© 1998 Nature America Inc. • http://neurosci.nature.com
© 1998 Nature America Inc. • http://neurosci.nature.com
articles
explore temporal information processing, and we showed that
the temporal response properties of A1 neurons can be altered
markedly to refine or degrade the capacity of the cortex to
respond to rapid successive input events. We also showed that
this plasticity has a large capacity to exaggerate the representation of specific, heavily presented sensory input rates. Finally, we
demonstrated that A1 neuronal networks can generate spectrally and temporally selective responses and that these networks can
reorganize topographic representations of tone frequency with
no evident change in the representation of temporal information, or vice versa, all as an apparent function of the spectrotemporal structures and schedules of sensory inputs.
This striking capacity for learning-based revision of the basic
integration/segmentation times of the cortical processing machinery could result from plasticity of synaptic time constants, of
intrinsic temporal characteristics and/or of network dynamics12,17,21,42,46. Paired-pulse facilitation and slow inhibitory potentials, for example, almost certainly are important in the cortical
recovery of responsiveness following any brief stimulation12,23,24,40–42,47. NB-induced plasticity will provide a powerful experimental approach for relating the cortical representation
of temporal information to changes in basic cortical dynamics
that shape the cortical responses to time-varying stimuli.
Methods
PREPARATION. Platinum bipolar stimulating electrodes were lowered
7 mm below the cortical surface, 3.3 mm lateral and 2.3 mm posterior
to bregma in barbiturate-anesthetized female rats (~300 g) and cemented into place using sterile techniques approved under UCSF Animal Care
Facility protocols. After two weeks of recovery, trains of six 25-ms tones
were paired with 200 ms of NB electrical stimulation in a sound-shielded, calibrated test chamber (five days per week). The frequency of the
tone was either one of seven frequencies (1.3, 2, 3, 5, 9, 14 or 19 kHz) or
was fixed (9 kHz). Tone amplitude was 20–30 dB above the minimum
rat hearing threshold48. In experiments using multiple carrier frequencies,
the frequency of the tones within each train was constant, whereas the
frequencies used from train to train were randomly varied. The tone pips
in stimulus trains were presented in a given rat at 5, 7.5 or 15 pps. Electrical stimulation began with the onset of the fourth tone. The stimulating current level (70–150 µA) was the minimum necessary to
desynchronize the EEG during slow-wave sleep for 1–2 seconds. Stimulation consisted of 100-pps capacitatively coupled biphasic pulses of 0.1ms duration. Several microdialysis studies have shown that this
stimulation protocol results in the release of cortical acetylcholine49,50.
Either cholinergic antagonists or lesions of the cholinergic cells in the
NB with 192 immunoglobulin G-saporin are sufficient to block this plasticity generated by NB stimulation8,9. Tonal and electrical stimuli did not
evoke any observable behavioral responses (that is, they did not cause
rats to stop grooming, or if sleeping, to awaken).
ELECTROPHYSIOLOGY. Twenty-four hours after the last pairing, animals
were anesthetized with sodium pentobarbital, the right auditory cortex
was surgically exposed, and neural responses were recorded with parylene-coated tungsten microelectrodes (FHC #070-02-01, 2 MΩ). Because
we used barbiturate anesthesia, the modulation of responses recorded in
this study may not be identical to the responses of awake animals. Penetration sites were chosen to evenly sample the cortical surface while avoiding blood vessels. To minimize the possibility of experimenter bias or
response variability due to variable recording depth, at every penetration site the electrode was lowered to ~550 µm below the pial surface
(layers 4/5), which yielded vigorous driven responses. Frequency/intensity response areas were reconstructed in detail by presenting 45 pure
tone frequencies (50-ms duration, 3-ms ramps) at each of 15 sound
intensities to the contralateral ear at a rate of 2 stimuli per s. The evoked
spikes of a neuron or a small cluster of 2–5 neurons were collected at
each site. Primary auditory cortex was defined on the basis of the short
latency (8–20 ms) of its evoked neuronal spike responses and its contin730
uous tonotopy. (Best frequency increases from posterior to anterior.)
Responsive sites that had clearly discontinuous best frequencies, along
with long-latency responses, high thresholds or very broad tuning were
considered to be non-A1 sample sites and were not included in these
sample data.
To determine the RRTF for each site, six tones (25 ms with 5-ms
ramps, 70 dB SPL) were presented twelve times at each of sixteen repetition rates. To minimize adaptation effects, repetition rates were randomly
interleaved, and two seconds of silence separated each train. The twosecond interval between trains allowed the response strength to 0.5-pps
trains to be approximated. RRTFs were defined using the tone frequency of the seven presented during the pairing period that was closest to
the best frequency of each site. To reduce the variability resulting from
different numbers of neurons included in different ‘multi-unit’ responses recorded in this study, response amplitude was normalized using the
number of spikes evoked at each site to an isolated tone. The normalized
RRTF was defined as the average number of spikes evoked for each of
the last five tones in the train divided by the number of spikes evoked by
the first tone in the train. Thus, a normalized spike rate of one indicates
that, at the given repetition rate, each of the tones in the train, on average,
evoked the same number of spikes as the first tone. Values greater than
one indicate facilitation; values less than one indicate response adaptation.
Only spikes occurring from 5–40 ms after each tone onset were used to
calculate the RRTF. The RRTF data could not be viewed on-line and were
analyzed only after each experiment was completed. All analyses were
automatized and therefore were not subject to experimenter bias or error.
The effect of NB pairing on mean RRTF across all conditions was determined with analysis of variance; pairwise comparisons were analyzed by
Fisher’s PLSD (protected least significant differences) test.
Acknowledgements
This work was supported by NIH grant NS-10414, ONR grant N00014-96-102,
Hearing Research Inc. and an NSF predoctoral fellowship. We thank
H.W. Mahncke, R.C. deCharms and C.E. Schreiner for technical advice, and
S.S. Nagarajan, W.J. Martin, D.V. Buonomano, P. Bedenbaugh, A.I. Basbaum,
K. Miller, C.E. Schreiner and E. Knudsen for comments on the manuscript.
RECEIVED 18 JUNE: ACCEPTED 30 SEPTEMBER 1998
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